Development and characterization of nifedipine amino methacrylate copolymer solid dispersion powders with various adsorbents Original Research Paper Development and characterization of nifedipine amin[.]
ARTICLE IN PRESS asian journal of pharmaceutical sciences ■■ (2017) ■■–■■ Available online at www.sciencedirect.com ScienceDirect j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / a j p s Original Research Paper Development and characterization of nifedipine-amino methacrylate copolymer solid dispersion powders with various adsorbents Yotsanan Weerapol a,b, Sontaya Limmatvapirat a,c, Jurairat Nunthanid a,c, Srisuda Konthong a, Supakij Suttiruengwong d, Pornsak Sriamornsak a,c,* a Pharmaceutical Biopolymer Group (PBiG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand Faculty of Pharmaceutical Sciences, Burapha University, Chonburi 20131, Thailand c Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand d Department of Materials Science and Engineering, Faculty of Engineering and Industrial Technology, Silpakorn University, Nakhon Pathom 73000, Thailand b A R T I C L E I N F O A B S T R A C T Article history: Solid dispersions of nifedipine (NDP), a poorly water-soluble drug, and amino methacry- Received November 2016 late copolymer (AMCP) with aid of adsorbent, that is, fumed silica, talcum, calcium carbonate, Received in revised form titanium dioxide, and mesoporous silica from rice husks (SRH), were prepared by solvent December 2016 method The physicochemical properties of solid dispersions, compared to their physical Accepted 12 January 2017 mixtures, were determined using powder X-ray diffractometry (PXRD) and differential scan- Available online ning calorimetry (DSC) The surface morphology of the prepared solid dispersions was examined by scanning electron microscopy (SEM) The dissolution of NDP from solid dis- Keywords: persions was compared to NDP powders The effect of adsorbent type on NDP dissolution Solid dispersion was also examined The dissolution of NDP increased with the ratio of NDP:AMCP:adsorbent Poorly water-soluble drug of 1:4:1 when compared to the other formulations As indicated from PXRD patterns, DSC Nifedipine thermograms and SEM images, NDP was molecularly dispersed within polymer carrier or Amino methacrylate copolymer in an amorphous form, which confirmed the better dissolution of solid dispersions Solid Adsorbent dispersions containing SRH provided the highest NDP dissolution, due to a porous nature Mesoporous silica from rice husks of SRH, allowing dissolved drug to fill in the pores and consequently dissolve in the medium The results suggested that solid dispersions containing adsorbents (SRH in particular) demonstrated improved dissolution of poorly water-soluble drug when compared to NDP powder © 2017 Shenyang Pharmaceutical University Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/) * Corresponding author Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand Fax: +66 34 255801 E-mail address: sriamornsak_p@su.ac.th (P Sriamornsak) http://dx.doi.org/10.1016/j.ajps.2017.01.002 1818-0876/© 2017 Shenyang Pharmaceutical University Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Yotsanan Weerapol, et al., Development and characterization of nifedipine-amino methacrylate copolymer solid dispersion powders with various adsorbents, Asian Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ajps.2017.01.002 ARTICLE IN PRESS asian journal of pharmaceutical sciences ■■ (2017) ■■–■■ Introduction The oral drug administration is the most preferred route of drug delivery due to convenience, patient adherence and rational production investment of oral solid dosage forms After oral ingestion, the drug must be liberated and then solubilized in gastrointestinal (GI) fluid before it can be absorbed and has a systemic effect Poor solubility of drug in GI medium generally leads to low dissolution rate and insufficient bioavailability [1,2] The selection of suitable formulation is of great significance in the development of successful product for oral administration of poorly water-soluble drugs Several formulation approaches can be used to improve the bioavailability of poorly water-soluble drugs The most common method of increasing dissolution rate is to reduce the size of solid drug particles, which leads to an increased surface area available for dissolution [3] The dissolution rate can also be increased by inducing salt formation or prodrug synthesis, which the new chemical entity has better solubility profiles but the same pharmaceutical activity after absorption in systemic [4,5] Another common method of improving bioavailability for the poorly soluble drugs is to prepare an amorphous formulation allowing faster drug dissolution in comparison to its corresponding crystalline form Solid dispersion is known as one of the effective methods for preparing amorphous solids and can be used for enhancing dissolution rate of poorly water-soluble drugs [6] The mechanism of dissolution enhancement of solid dispersions can be explained by the transformation of a stable crystalline drug into a less stable amorphous state, a reduction in drug particle size and an increase in wettability and solubility of drug surrounded by hydrophilic carriers, such as polyethylene glycol, hydroxypropylcellulose and polyvinylpyrrolidone [1,2,7] Amino methacrylate copolymer (AMCP) is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate It can be dissolved in gastric fluid up to pH 5.0 and swelled above pH 5.0 Previously, AMCP was used as a carrier for solid dispersions, for example, chlordiazepoxide-AMCP solid dispersions [8] It was observed that all AMCP-based solid dispersion formulations produce higher dissolution rate than the physical mixtures and the pure chlordiazepoxide Li et al [9] prepared solid dispersions of curcumin using AMCP as a matrix carrier by simple solution mixing method They found that the solubility of curcumin was increased by forming curcumin-AMCP solid dispersions Nevertheless, the prepared solid dispersions of AMCP tend to be sticky or tacky, resulting from the intermolecular interaction of eutectic composition between drug and polymer [10] This leads to a decrease in the yield of solid dispersions and results in inconvenience handling in the subsequent manufacturing process Recently, adsorbents (e.g., fumed silica (FS), magnesium aluminum silicate, etc.) have been extensively applied as carriers in fabrication of solid dispersions to improve dissolution of poorly water-soluble drugs [11] In general, adsorbents are used when there is a need to add a liquid or semisolid ingredient in the formulation; adsorbents are capable of sorbing the liquid component onto the dry powder Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phos- phate, kaolin, magnesium carbonate, magnesium silicate, magnesium oxide, starch and silicon dioxide By using the adsorbents, the melt of solid dispersion could be adsorbed in the pores and/or rough surface of absorbents, thus improving powder flowability and compressibility for further manufacturing processes [7,12–14] In our preliminary study, the solid dispersions composed of nifedipine (NDP), AMCP and FS were developed (at ratios of NDP:AMCP:FS = 1:0.5–4:0–1) [15] With no FS, gelatinous mass of solid dispersions was obtained.The free-flowing powder was achieved when inert FS was added The results from dissolution test revealed poor and slow dissolution of pure NDP On the other hand, solid dispersions with low amount of AMCP (i.e., the ratios of 1:0.05:1, 1:1:1 and 1:2:1) showed an improved drug dissolution Nevertheless, the dissolution profiles of these solid dispersions resulted in slow release with drug dissolution about 20–30% after h.The enhanced drug dissolution was observed when high amount of AMCP (at a ratio of NDP to AMCP of 1:4) was used, regardless of the addition of adsorbent [15] However, the influence of the type of adsorbents on drug dissolution has not been investigated in details Therefore, in this research, the powder form of solid dispersions was developed using various types of adsorbents Solid state characterization, i.e., powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM), was performed The influence of NDP:AMCP:adsorbent on drug dissolution was also evaluated Materials and methods 2.1 Materials NDP was purchased from Xilin Pharmaceutical Raw Material Co., Ltd (Jiangsu, China) AMCP (Eudragit® E) and FS (Aerosil® 200) were received from Evonik Industries (Hanau, Germany) Mesoporous silica from rice husks (referred to as SRH) was prepared by depolymerization at high temperature, as described in previous report [16] Simulated gastric fluid USP without pepsin (SGF) was prepared by dissolving g of sodium chloride and mL of hydrochloric acid with distilled water to make a total volume of 1000 mL of solution All other chemicals used in this study were of pharmaceutical grade and used as received without further purification 2.2 Preparation of NDP-AMCP solid dispersions with adsorbents Solid dispersions of NDP and AMCP with various adsorbents were prepared by solvent method NDP (1 g) and various amounts of AMCP were dissolved in sufficient amount of methylene chloride to obtain a clear solution, and various amounts of different adsorbents were then added to obtain uniform suspensions After mixing, the solvent was removed at ambient temperature (25 °C) The solid dispersion obtained was dried at 40 °C in a vacuum oven for 24 h In this study, the adsorbents investigated were FS, SRH, titanium dioxide (TiO2), calcium carbonate (CaCO3), and talcum The NDP, AMCP and adsorbent ratios were 1:0.5:1, 1:1:1, 1:2:1, 1:4:1 and Please cite this article in press as: Yotsanan Weerapol, et al., Development and characterization of nifedipine-amino methacrylate copolymer solid dispersion powders with various adsorbents, Asian Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ajps.2017.01.002 ARTICLE IN PRESS asian journal of pharmaceutical sciences ■■ (2017) ■■–■■ 1:4:0 Physical mixtures (PM), at the same ratios to solid dispersions, were also prepared by physical mixing the accurately weighed amount of NDP, AMCP and adsorbent thoroughly using a vortex mixer until homogeneous mixture was obtained All samples were kept in desiccator until further study 2.3 Characterization 2.3.1 Moisture content determination ⎛ (W − Wd ) ⎞ Moisture content (% ) = ⎜ m ⎟⎠ × 100 ⎝ Wd (1) where Wm is the moist weight (g) and Wd is the dry weight (g) 2.3.2 Determination of flow properties Angle of repose was performed on fixed and free of vibration base The powder layer after falling from the funnel was retained [18] The symmetrical cone of powder was built up under the funnel Angle of repose (α) was determined from measuring the height of the cone powder and diameter of base by the following equation height tan (α ) = 0.5 base (2) Compressibility index and Hausner ratio were also determined by tapping the powder in cylinder [18] The equations use the unsettled apparent volume (Vo) and the final tapped volume (Vf) of the powder after tapping the sample until no further volume changes occur in measuring cylinder Compressibility index and Hausner ratio were determined by Equations (3) and (4), respectively ⎡ Vo + Vf ⎤ Compressibility index = 100 × ⎢ ⎣ Vo ⎥⎦ Hausner ratio = 2.3.3 Vo Vf (3) (4) DSC analysis The DSC analysis was carried out using differential scanning calorimeter (model Sapphire, Perkin Elmer, Germany) About 2–3 mg of samples were accurately weighed, placed in an aluminum pan and sealed with an aluminum lid Sample was heated from 25 to 200 °C at a heating rate of 10 °C/min 2.3.4 PXRD analysis The PXRD experiments were performed using a powder X-ray diffractometer (model Miniflex II, Rigaku Co., Japan) at 30 kV, 15 mA over the range of 5–45° 2θ at the scanning speed of degrees/min using CuKα radiation wavelength of 1.5406 Å 2.3.5 microscope (model Maxim-2000, CamScan Analytical Ltd., England), under accelerating voltage of 15 keV Samples were fixed on SEM stub with double-sided adhesive tape and then coated in a vacuum with thin gold layer before investigation 2.4 Moisture content of solid dispersions was carried out with moisture analyzer (model MA45, Sartorius, Germany) Solid dispersions (approximately g) were placed in a ventilated oven at 105 °C until reaching a constant weight [17] Then, the moisture content was calculated by the following equation SEM observation The surface morphology of solid dispersions, raw materials and physical mixtures was observed by using a scanning electron Dissolution test The dissolution of NDP from samples (equivalent to 10 mg of NDP) was performed in 900 mL SGF, pH 1.2, at 37 ± 0.5 °C using USP dissolution apparatus II (model DT70, Erweka, Germany) with paddle rotation speed of 50 rpm Samples were withdrawn from the dissolution vessels at 5, 10, 15, 30, 60, 90 and 120 and passed through 0.45-μm nylon filter and then analyzed by high performance liquid chromatography (HPLC; model Jasco PU2089 plus quaternary gradient inert pump, and a Jasco UV-2070 plus multi wavelength UV–vis detector, Jasco, Japan) at a wavelength of 235 nm using ACEđ (4.6 ì 250 mm) column.The system was operated under isocratic flow at mL/min using a mobile phase consisting of water:acetonitrile:methanol; 50:25:25 (v/v), filtered through a 0.45-μm membrane filter, and degassed in a sonicator bath before used Sample injection volume was 20 μL Data were collected and analyzed by ChromNav program (Jasco, Japan) The experiments were conducted in triplicate 2.5 Statistical analysis Analysis of variance (ANOVA) and Levene’s test for homogeneity of variance were carried out using SPSS version 10.0 for Windows (SPSS Inc., USA) Post hoc testing (P < 0.05) of multiple comparisons was performed by either the Scheffé or Games-Howell test depending on whether Levene’s test was insignificant or significant, respectively Results and discussion 3.1 Physicochemical characterization of solid dispersions By using solvent method with the aid of adsorbent, the fine particles of all solid dispersion formulations were obtained.The moisture content of all solid dispersion formulations ranged from 2% to 6% A small amount of water ( 0.05) Conclusion Solid dispersions of a poorly water-soluble drug (i.e., NDP) were successfully prepared by solvent method using AMCP with the aid of adsorbents An improved dissolution of NDP has been attributed to changes in crystal structure, which were demonstrated by the results of DSC and PXRD studies Furthermore, the free-flowing powder and enhanced dissolution behavior were obtained by addition of 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Yotsanan Weerapol, et al., Development and characterization of nifedipine- amino methacrylate copolymer solid dispersion powders with various adsorbents, Asian Journal of Pharmaceutical Sciences... Yotsanan Weerapol, et al., Development and characterization of nifedipine- amino methacrylate copolymer solid dispersion powders with various adsorbents, Asian Journal of Pharmaceutical Sciences